Stroke prevention and control system in China: CSPPC-Stroke Program.

In China, stroke is a major cause of mortality, and long-term physical and cognitive impairment. To meet this challenge, the Ministry of Health China Stroke Prevention Project Committee (CSPPC) was established in April 2011. This committee actively promotes stroke prevention and control in China. With government financial support of 838.4 million CNY, 8.352 million people from 536 screening points in 31 provinces have received stroke screening and follow-up over the last seven years (2012-2018). In 2016, the CSPPC issued a plan to establish stroke centers. To shorten the pre-hospital period, the CSPPC established a stroke center network, stroke map, and stroke "Green Channel" to create three 1-h gold rescue circles, abbreviated as "1-1-1" (onset to call time <1 h; pre-hospital transfer time < 1 h, and door-to-needle time < 1 h). From 2017 to 2018, the median door-to-needle time dropped by 4.0% (95% confidence interval (CI), 1.4-9.4) from 50 min to 48 min, and the median onset-to-needle time dropped by 2.8% (95% CI, 0.4-5.2) from 180 min to 175 min. As of 31 December 2018, the CSPPC has established 380 stroke centers in mainland China. From 1 November 2018, the CSPPC has monitored the quality of stroke care in stroke center hospitals through the China Stroke Data Center Data Reporting Platform. The CSPPC Stroke program has led to a significant improvement in stroke care. This program needs to be further promoted nationwide.

Recurrent epithelioid malignant peripheral nerve sheath tumor with neurofibromatosis type 1: A case report and literature review.

Malignant peripheral nerve sheath tumors (MPNSTs) are unusual and aggressive malignant soft-tissue tumors that comprise 5-10% of all soft-tissue sarcomas. Approximately 50% of MPNST cases are associated with neurofibromatosis type-1 (NF-1). As a rare MPNST subset, the epithelioid variant of MPNST (eMPNST) is histologically characterized by the predominant presence of epithelioid tumor cells, and accounts for <5% of all MPNSTs. In addition, eMPNST is rarely associated with NF-1 when compared with conventional MPNST. Although extensive clinicopathological studies have been conducted on eMPNST, clinicians face difficulty when attempting to make an accurate diagnosis. Subsequently, the biological consequences, including recurrence, metastasis and mortality rate in patients with eMPNST remain unclear. The current study presents the case of a 71-year-old woman with eMPNST and a family history of NF-1 in whom tumors had recurred twice on the lower back. A literature search for eMPNSTs was conducted by browsing PubMed and MEDLINE for English-language articles, as well as references from review articles, and revealed 129 published cases. Only 5 cases of eMPNST were associated with NF-1. The studies were retrospectively reviewed and the clinicopathological data of the patients, including tumor site, treatment, follow-up, prognosis, and immunohistochemical positivity were collected.

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.

CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling.

Polycomb chromobox (CBX) proteins are involved in gene silencing to function as oncogenes or tumor suppressors through the polycomb repressive complex (PRC1). CBX4 has been implicated in the progression of human cancers, but its role and clinical significance in breast cancer remain unclear. Here, we show that CBX4 is up-regulated in breast cancer and exerts oncogenic activities via miR-137-mediated activation of Notch1 signaling pathway. CBX4 expression was increased in breast cancer, compared with the nontumorous tissues. High CBX4 expression was closely correlated with tumor metastasis, advanced clinical stage and poor overall survival in a cohort of 179 patients with breast cancer. In vitro studies demonstrated that CBX4 overexpression enhanced, whereas CBX4 knockdown inhibited cell growth and migration. Mechanistically, in a PRC1-dependent manner, CBX4 inhibited the promoter activity of miR-137 and suppressed its expression. miR-137 decreased the expression of Notch1, Jag1 and Hey2 via targeting their 3'-UTRs. The suppression of Notch1 by siRNA or overexpression of miR-137 markedly attenuated CBX4-promoted phenotypes. Collectively, these findings indicate that CBX4 promotes breast cancer via miR-137-mediated Notch1 signaling. Our data, therefore, suggest that CBX4 serve as a prognostic biomarker and that targeting CBX4/miR-137 axis may provide therapeutic potent in the treatment of breast cancer.

Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.

Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aß) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1-green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aß accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain.

Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages.

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages.

Hereditary endotheliopathy with retinopathy and encephalopathy: pathological and genetic studies of a family.

BACKGROUND: The objective of this study was to examine the clinical, pathological and genetic features of a family suffering from hereditary endotheliopathy with retinopathy and encephalopathy. METHODS: The index case was male, and his symptoms were detected at 18 years of age. The clinical manifestation included recurrent headache, fever, consciousness disturbances and haemiplegia. Bilateral cerebral hemispheric lesions were detected via MRI as low signals on T1 and high signals on T2 and FLAIR, with moderate enhancement. Video EEG revealed an increase in the slow wave frequency. An EMG displayed neurogenic atrophy. Similar clinical and imaging characteristics were detected in his mother and his uncle. Pathological examinations of the brain, muscle and sural nerve were performed on the index case. Sequence analysis of the TREX1 gene was performed on the index case, his sister and his father. RESULTS: A brain biopsy revealed spongiform alterations as well as inflammatory cell infiltration in a few small vessels. Neurogenic muscular atrophy was detected based on a biopsy of the muscle. Demyelination was detected based on a biopsy of the sural nerve. Electron microscopic examination of the sural nerve revealed thickening and delamination of the basement membrane. No reported TREX1 gene mutation was detected for any of the patients. CONCLUSION: Hereditary endotheliopathy presented with peripheral nerve involvement. Multi-laminar thickening of the basement membrane of the capillaries also appeared in the extracerebral tissue. The involvement of a novel gene should be further examined.

Peroxisome proliferator-activated receptor-γ agonist pioglitazone ameliorates white matter lesion and cognitive impairment in hypertensive rats.

AIMS: Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats. METHODS: Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected. RESULTS: Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1ß and TNF-α in the white matter. CONCLUSIONS: Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.

Beclin 1 knockdown retards re-endothelialization and exacerbates neointimal formation via a crosstalk between autophagy and apoptosis.

OBJECTIVE: Endothelial regeneration is an essential process for the prevention of excessive neointimal formation following endothelial denudation. Beclin 1, a mammalian autophagy gene, is a link between autophagy and apoptosis. We hypothesized that the interference of Beclin 1 can influence re-endothelialization and ultimately affect neointimal formation by regulating autophagy and apoptosis. METHODS: A rat carotid injury model of endothelial denudation was used, and small interfering RNA of Beclin 1 was perivascularly administered. Neointima was evaluated by morphological analysis. von Willebrand factor, Beclin 1, LC3, autophagic substrate p62 and caspase-3 levels were detected by immunofluorescence or Western blotting. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling assay was performed to evaluate apoptosis. RESULTS: Carotid injury induced an upregulation of Beclin 1 protein which was down regulated by more than 50% with small RNA interference. Beclin 1 knockdown significantly retarded re-endothelialization 7 days after injury and subsequently augmented neointima by more than 2 folds at 14 and 21 days. Autophagy and apoptosis were detected to reveal the regulatory effect of Beclin 1. The injury-activated autophagy, shown by the increased levels of punctate LC3 and LC3II as well as decreased p62 expression, was significantly inhibited by Beclin 1 knockdown. Meanwhile, the apoptotic endothelial cell number was increased and caspase-3 was up-regulated, though the expression of truncated BID was not significantly influenced. CONCLUSION: Beclin 1 knockdown exacerbated neointimal formation after rat carotid injury, associated with retarded re-endothelialization due to enhanced apoptosis, while simultaneously prohibiting autophagic activation. The data suggested an essential role of Beclin 1 as a regulator between autophagy and apoptosis in the setting of neointimal formation.

Protective effects of puerarin against Aß40-induced vascular dysfunction in zebrafish and human endothelial cells.

Aß40-induced vascular dysfunction has been implicated in the pathogenesis of Alzheimer׳s disease (AD). In the present study, we investigated the possible protective effects of puerarin against Aß40-induced vascular damage and impairment to angiogenesis in transgenic TG (fli1:EGFP) zebrafish and human endothelial cells. Aß40 peptides at 5µM caused an obvious reduction of vessel branches in the subintestinal vein basket, induced NADPH oxidase-derived reactive oxygen species and impaired vascular endothelial growth factor (VEGF)-dependent angiogenesis. Pretreatment with puerarin attenuated Aß40-induced vessel reduction and impairment to angiogenesis in a dose-dependent manner. In addition, Aß40 decreased VEGF-dependent phosphorylation of Akt and eNOS, whereas puerarin treatment attenuated these detrimental effects. Furthermore, the restoration of Aß40-induced-angiogenesis impairment by puerarin was abolished by either the PI3 kinase inhibitor LY294002 (10µM) or eNOS inhibitor L-NAME. The present study suggests that puerarin exerts its protective action probably through reduction of NADPH oxidase-derived reactive oxygen species overproduction and activation of the PI3K/Akt/eNOS pathways.

Inordinate glucose variation poststroke is associated with poor neurological improvement in patients without history of diabetes.

INTRODUCTION: Glucose variation is an important risk factor for the complications of diabetes mellitus. The plasma glucose level poststroke is in continuous fluctuation. However, whether the variation influences neurological improvement remains unknown. AIMS: This observational study aimed to investigate the association of glucose variation with neurological improvement poststroke. METHODS: We consecutively enrolled 216 ischemic stroke patients with no history of diabetes mellitus within 72 h of onset, with instant blood glucose <11.1 mmol/L at admission. The glucometabolic status was evaluated by an oral glucose tolerance test 1 day after admission and 14 days after stroke, respectively. The severity of neurological deficit was assessed with the National Institute of Health Stroke Scale (NIHSS). RESULTS: Fourteen days after stroke, 31% patients were found to have impaired glucose tolerance and 30.6% were newly diagnosed diabetes mellitus by oral glucose tolerance test. A higher level of instant blood glucose at admission or fasting plasma glucose (FPG) at 1 day correlated with a less neurological improvement. The number of patients with no <20% decrease in NIHSS was significantly decreased in patient group with higher than 30% variation of either FPG or 2-h postprandial glucose. Similar correlation between glucose variation and neurological improvement was also found in 117 patients with 2-h postprandial glucose ≥7.8 mmol/L at 1 day. CONCLUSIONS: Inordinate glucose variation correlated with less neurological improvement poststroke, giving the evidence that the fluctuation of glucose levels in stroke patients should be taken into consideration during glucose modulation.

Neuroprotective effect of chondroitinase ABC on primary and secondary brain injury after stroke in hypertensive rats.

Focal cerebral infarction causes secondary damage in the ipsilateral ventroposterior thalamic nucleus (VPN). Chondroitin sulfate proteoglycans (CSPGs) are a family of putative inhibitory components, and its degradation by chondroitinase ABC (ChABC) promotes post-injury neurogenesis. This study investigated the role of ChABC in the primary and secondary injury post stroke in hypertension. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), and were subjected to continuous intra-infarct infusion of ChABC (0.12 U/d for 7 days) 24 h later. Neurological function was evaluated by a modified neurologic severity score. Neurons were counted in the peri-infarct region and the ipsilateral VPN 8 and 14 days after MCAO by Nissl staining and NeuN labeling. The expressions of CSPGs, growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were detected with immunofluorescence or Western blotting. The intra-infarct infusion of ChABC, by degrading accumulated CSPGs, rescued neuronal loss and increased the levels of GAP-43 and SYN in both the ipsilateral cortex and VPN, indicating enhancd neuron survival as well as augmented axonal growth and synaptic plasticity, eventually improving overall neurological function. The study demonstrated that intra-infarct ChABC infusion could salvage the brain from both primary and secondary injury by the intervention on the neuroinhibitory environment post focal cerebral infarction.

Association between improved trunk stability and walking capacity using ankle-foot orthosis in hemiparetic patients with stroke: evidence from three-dimensional gait analysis.

BACKGROUND: Restoration of both normal movement of the pelvis and centre of mass is a primary goal of walking rehabilitation in post-stroke patients because these movements are essential components of effective gait. The aim of this study is to quantitatively analyze the effect of ankle-foot orthosis on walking ability, and to investigate the correlation between improvements in trunk motion and walking capacity. METHODS: Walking speed, centre of mass displacement, and pelvic movements were examined in 20 post-stroke hemiparetic patients with and without ankle-foot orthosis using three-dimensional motion analysis. RESULTS: Using ankle-foot orthosis improved walking speed, pelvic rotation and tilt, and lateral and vertical displacements of the centre of mass (P < 0.01). Moreover, the gait asymmetry index was significantly decreased (P < 0.01), and the Functional Ambulation Categories score improved significantly when patients used an ankle-foot orthosis (P < 0.05). There was significant correlation between improvements in the walking capacity and the displacement of the centre of mass in both vertical and lateral directions (P < 0.01). CONCLUSIONS: Using ankle-foot orthosis improves the walking capacity by improving the stability and concordant of the trunk in hemiplegic patients. The improvement in the walking capacity from using an ankle-foot orthosis may be attributed to its prevention of foot drop and compensation for the instability of the ankle joint.

Stroke-prone renovascular hypertensive rat as an animal model for stroke studies: from artery to brain.

High blood pressure is a main risk factor for both initial and recurrent stroke. Compared to the post stroke situation in normotension, the brain lesion is larger in hypertension, and the treatments may not be as effective. Thus, the results from healthy individuals may not be directly applied to the hypertensive. In fact, the high prevalence of hypertension in stroke patients and its devastating effect urge the necessity to integrate arterial hypertension in the study of stroke in order to better mimic the clinical situations. The first step to do so is to have an appropriate hypertensive animal model for stroke studies. Stroke-prone renovascular hypertensive rat (RHRSP) introduced in 1998, is an animal model with acquired hypertension independent of genetic deficiency. The blood pressure begins to increase during the first week after constriction of bilateral renal arteries, and becomes sustained since around the 3rd month. Because the morphological and physiological changes of cerebral arteries are similar to those in hypertensive patients, the rats represent a higher than 60% incidence of spontaneous stroke. The animal model has several advantages: one hundred percent development of hypertension without gene modification, high similarity to human hypertension in cerebrovascular pathology and physiology, and easy establishment with low cost. Thus, the model has been extensively used in the investigation of ischemic stroke, and has been shown as a reliable animal model. This paper reviewed the features of RHRSP and its applications in the treatment and prevention of stroke, as well as the investigations of secondary lesions postischemic stroke.

Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways.

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

LRRK2 A419V is not associated with Parkinson's disease in different Chinese populations.

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.

A method of evaluating the lower limit of cerebral autoregulation and its correlation with blood pressure by transcranial Doppler in rats.

The aim of present study was to validate the assessment of lower limit of cerebral autoregulation (LLCA) as derived from mean artery blood pressure (MABP) and cerebral zero flow pressure (ZFP) by means of transcranial Doppler (TCD) and to determine the accurate relationship between LLCA and MABP in stroke-prone renovascular hypertensive rats (RHRSP). We studied two groups of rats: RHRSP and normal controls. Blood flow velocity of middle cerebral artery was monitored by TCD and arterial blood pressure was recorded in right femoral artery to compute the ZFP. The value of LLCA was determined as the difference between MABP and ZFP and validated by the value determined by blood withdrawal-induced cerebral autoregulation. In normal rats, the LLCA derived from the new method was 69.8 ± 8.7 mm Hg, from the change of blood velocity was 69.4 ± 9.8 mmHg and from blood volume flow after blood withdrawal was 68.8 ± 9.7 mmHg. In the RHRSP group, the corresponding values of LLCA were 109.1 ± 17.2 mm Hg, 110.0 ± 18.0 mm Hg and 109.0 ± 19.3 mm Hg, respectively. In each group, there was no statistically significant difference among the three values. LLCA in RHRSP began to increase 6 weeks after hypertension-induced operation, significantly higher than controls (p < 0.05), and stabilized at 110 mm Hg, 10 weeks after operation. The increase of LLCA was positively correlated with MABP, following an "S" curve, demonstrating that the change of LLCA was more obvious in the middle range of MABP in RHRSP (R(2) = 0.8848, p < 0.05). In conclusion, TCD is a valid and noninvasive method for determination of LLCA compared with the classic method in rats. Our data demonstrated that the change of LLCA may be correlated with MABP, following an "S" curve relationship.